Project Summary Early mobility, the process of engaging patients in exercise and/or physical therapy during their clinical care, is a promising treatment for severe critical illnesses, such as acute respiratory failure (ARF), where it improves a variety of clinical and functional outcomes. How early mobility/exercise exacts these benefits, however, is unknown and understudied. This lack of knowledge is notable because the implementation of exercise/activity interventions in these populations is extremely challenging and resource intensive. Knowledge of the mechanisms underlying the beneficial effects of early mobility/exercise would provide specific cellular and molecular targets that would allow clinicians to refine interventions and stimulate development of exercise-mimetic therapeutics in settings where resources and personnel limit the application of classical mobility/exercise interventions. To address this knowledge gap, our goal in this application is to determine the mechanisms whereby exercise modulates systemic and end organ inflammation and damage in ARF. We will use reverse and forward translational approaches to realize this goal, building on our pre- clinical model of early mobility and human data in patients with lung injury. Based on strong preliminary data from these sources, we propose a hypothetical model in which a systemic inflammatory response during the early phase of critical illness, mediated via the IL-17/G-CSF axis, causes lung injury and skeletal muscle wasting secondary to immune cell infiltration and inflammation. Moreover, exercise applied during this phase lessens end-organ injury/wasting by specifically attenuating the systemic and local innate immune responses. We will examine these hypotheses in critically ill humans by leveraging an NHLBI-funded randomized controlled trial (NEXIS RCT, R01HL132887, NCT03021902) of early exercise and amino acid supplementation versus usual care in critically ill patients with ARF, as well as carefully selected animal models to extend our insights. As, the NEXIS RCT began recruitment in September 2017, we hope that the current application will be funded allowing us to capture most of the NEXIS participants for crucial biospecimen collection. We anticipate that our results will yield seminal, mechanistic knowledge of the beneficial effects of exercise to reduce systemic and end organ inflammation and, in turn, lung and skeletal muscle damage. Our results also hold the potential to identify a novel mechanism of exercise's systemic benefits through modulation of a novel myokine that alters the systemic and local inflammatory response. Our findings, therefore, will advance both basic scientific knowledge and clinical practice towards the goal of improving short-term clinical and long-term functional outcomes in patients with critical illness and other inflammatory conditions.